This is a competing continuation R01 proposal to support new biostatistical methodologic development and application of these new methods to individual level data on 11,939 adolescents in 42 existing or ongoing prevention and treatment intervention randomized trials aimed at depression. The central goal of our proposed work is the development and application of novel quantitative methods necessary to integrate findings across trials on preventing and treating depression in adolescence and their relevance for building and testing the next generation of comprehensive intervention strategies. Built on the past 22 years of NIH funding for the Prevention Science and Methodology Group (PSMG), this collaborative synthesis project will bring together expert methodologists and intervention scientists with the guidance of an external scientific advisory committee. The 42 prevention (n=24) and treatment (n=18) intervention trials we will use in this proposal focus on the child (e.g., cognitive behavioral, interpersonal therapy), parent/family (e.g., parent training), and/or antidepressants, each class known to have beneficial impact on adolescent depression. Our work will focus on examining the shared and unique mediators and moderators over these trials. Building on our data sharing agreements, we will conduct new cross-trial analyses of moderator effects involving demographic characteristics, symptomatology, and adversity across different clusters of prevention or treatment interventions. We will also examine the shared and unique mediational pathways of these interventions involving adherence/compliance, cognitive processes, and family processes. We propose new methodologic approaches to distinguish these shared and unique mediators and mediators using individual data across multiple trials. To minimize biases and maximize analytic comparability across trials, these new methods will account for individual and trial level differences in population/person level risk and protective factors, differences in the interventions including exposure, fidelity, or adherence, and differences in trial design including follow-up period, and assessment instruments. These new methodologic approaches are necessary because nearly all randomized trials are severely underpowered to address mediation or moderation within their own studies, and the statistical methods now available for data synthesis (e.g., meta-analysis), are not adequate for complex multi-trial analyses. In Aim 1 we develop new biostatistical multilevel, longitudinal models to synthesize cross-trial analyses on mediation and moderation across related randomized trials. In Aim 2 we apply these methods to trials on depression interventions for adolescents. In Aim 3 we identify key gaps in our understanding of intervention efficacy to be addressed in the next generation of intervention trials, and develop scientific guidelines. PUBLIC HEALTH RELEVANCE: Depression is the single leading cause of disability, and from a developmental perspective, its prevention or treatment during adolescence can provide lifelong benefits. Despite the existence of generally efficacious prevention and treatment interventions for depression, we have yet to assimilate this knowledge into personalized strategies that meet the public health needs of diverse populations to meet their acute as well as longer term risk for recurrence. This work will specify who can benefit from different intervention options across time and provide the knowledge to build effective personalized as well as contextualized interventions to address depression in adolescence.